TY - JOUR
T1 - Developmental Profile of Psychiatric Risk Associated With Voltage-Gated Cation Channel Activity
AU - Clifton, Nicholas E.
AU - Collado-Torres, Leonardo
AU - Burke, Emily E.
AU - Pardiñas, Antonio F.
AU - Harwood, Janet C.
AU - Di Florio, Arianna
AU - Walters, James T.R.
AU - Owen, Michael J.
AU - O'Donovan, Michael C.
AU - Weinberger, Daniel R.
AU - Holmans, Peter A.
AU - Jaffe, Andrew E.
AU - Hall, Jeremy
N1 - Funding Information:
This study was supported by the Medical Research Council (Grant Nos. MR/L010305/1 [to MJO] and MR/R011397/1 [to JH] ) and a Wellcome Trust (204824/Z/16/Z [to NEC] and 100202/Z/12/Z [to MJO, JH]).
Funding Information:
We thank the Bipolar Disorder and Major Depressive Disorder workgroups of the Psychiatric Genomics Consortium for providing summary statistics used in this study. We would like to thank the research participants and employees of 23andMe for making this work possible. We thank R. Zielke, R.D. Vigorito, and R.M. Johnson of the National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland for providing fetal, child, and adolescent brain specimens. We also acknowledge the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories, and the National Institute of Mental Health (NIMH) Human Brain Collection Core. Lastly, we thank the CommonMind Consortium: Pamela Sklar and Joseph Buxbaum (Icahn School of Medicine at Mount Sinai), Bernie Devlin and David Lewis (University of Pittsburgh), Raquel Gur and Chang-Gyu Hahn (University of Pennsylvania), Keisuke Hirai and Hiroyoshi Toyoshiba (Takeda Pharmaceuticals Company Limited), Enrico Domenici and Laurent Essioux (F. Hoffman-La Roche Ltd), Lara Mangravite and Mette Peters (Sage Bionetworks), and Thomas Lehner and Barbara Lipska (NIMH).
Funding Information:
This study was supported by the Medical Research Council (Grant Nos. MR/L010305/1 [to MJO] and MR/R011397/1 [to JH]) and a Wellcome Trust (204824/Z/16/Z [to NEC] and 100202/Z/12/Z [to MJO, JH]). We thank the Bipolar Disorder and Major Depressive Disorder workgroups of the Psychiatric Genomics Consortium for providing summary statistics used in this study. We would like to thank the research participants and employees of 23andMe for making this work possible. We thank R. Zielke, R.D. Vigorito, and R.M. Johnson of the National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland for providing fetal, child, and adolescent brain specimens. We also acknowledge the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer's Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories, and the National Institute of Mental Health (NIMH) Human Brain Collection Core. Lastly, we thank the CommonMind Consortium: Pamela Sklar and Joseph Buxbaum (Icahn School of Medicine at Mount Sinai), Bernie Devlin and David Lewis (University of Pittsburgh), Raquel Gur and Chang-Gyu Hahn (University of Pennsylvania), Keisuke Hirai and Hiroyoshi Toyoshiba (Takeda Pharmaceuticals Company Limited), Enrico Domenici and Laurent Essioux (F. Hoffman-La Roche Ltd), Lara Mangravite and Mette Peters (Sage Bionetworks), and Thomas Lehner and Barbara Lipska (NIMH). A previous version of this article was published as a preprint on bioRxiv: https://doi.org/10.1101/2020.10.19.345801. The authors report no biomedical financial interests or potential conflicts of interest.
Publisher Copyright:
© 2021 Society of Biological Psychiatry
PY - 2021/9/15
Y1 - 2021/9/15
N2 - Background: Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant. Methods: We aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used postmortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple prenatal and postnatal time points, with summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder, and major depressive disorder. We prioritized gene sets for overall enrichment of association with each disorder and then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage. Results: We observed relationships between the expression of genes involved in voltage-gated cation channel activity during early midfetal, adolescence, and early adulthood time points and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during early midfetal development and higher expression during adolescence and early adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, while for bipolar disorder, the relationship was distributed between calcium and potassium channel activity genes. Conclusions: Our results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.
AB - Background: Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant. Methods: We aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used postmortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple prenatal and postnatal time points, with summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder, and major depressive disorder. We prioritized gene sets for overall enrichment of association with each disorder and then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage. Results: We observed relationships between the expression of genes involved in voltage-gated cation channel activity during early midfetal, adolescence, and early adulthood time points and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during early midfetal development and higher expression during adolescence and early adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, while for bipolar disorder, the relationship was distributed between calcium and potassium channel activity genes. Conclusions: Our results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.
KW - Brain development
KW - Dorsolateral prefrontal cortex
KW - Genome-wide association studies
KW - Psychiatric disorders
KW - Transcriptome
KW - Voltage-gated cation channel activity
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U2 - 10.1016/j.biopsych.2021.03.009
DO - 10.1016/j.biopsych.2021.03.009
M3 - Article
C2 - 33965196
AN - SCOPUS:85111405651
SN - 0006-3223
VL - 90
SP - 399
EP - 408
JO - Biological psychiatry
JF - Biological psychiatry
IS - 6
ER -